title: A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome.
abstract: Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon;
authors.forename: Erica S
authors.initials: ES
authors.lastname: Levitt
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Hunnicutt
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Knopp
authors.forename: John T
authors.initials: JT
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: Bissonnette
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001049:Apnea / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects*; D015518:Rett Syndrome / Q000188:drug therapy* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D010880:Piperidines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D018698:Glutamic Acid; D011188:Potassium
keywords: Rett syndrome; apnea; serotonin